1. Field of the Invention (Technical Field)
The present invention relates to formulations, methods and kits for the delivery and administration of synthetic heparin-binding growth factor analogs, particularly for use in tissue repair, including bone and cartilage repair.
2. Description of Related Art
Note that the following discussion refers to a number of publications by author(s) and year of publication, and that due to recent publication dates certain publications are not to be considered as prior art vis-à-vis the present invention. Discussion of such publications herein is given for more complete background and is not to be construed as an admission that such publications are prior art for patentability determination purposes.
The use of various bone filler agents and compositions is well known. Among materials used are various calcium-containing compounds and compositions including demineralized bone matrix (DBM). Limited research has been conducted using compositions which include growth factors, including recombinantly-produced growth factors, such as recombinantly produced bone morphogenic protein-2 (BMP-2).
The role of other growth factors in tissue repair, such as transforming growth factor-alpha (TGF-α) or transforming growth factor-beta (TGF-β), has been studied. In particular, TGF-β is known to accelerate the wound repair process. TGF-β1 has been proposed as a likely candidate for stimulating cartilage repair as it affects chondrocytes by enhancing matrix production, cell proliferation, and osteochondrogenic differentiation. There are at least three isoforms of TGF-β in man, TGF-β1, TGF-β2, TGF-β3. TGF-β exists in at least five isoforms, known TGF-β1, TGF-β2, TGF-β3, TGF-β4 and TGF-β5, that are not related to TGF-α. Their amino acid sequences display homologies on the order of 70-80 percent. TGF-β1 is the prevalent form and is found almost ubiquitously while the other isoforms are expressed in a more limited spectrum of cells and tissues.
TGF-beta is the prototype of a family of proteins known as the TGF-beta superfamily. This family includes inhibins, Activin A, MIS (Mullerian activating substance) and BMPs (Bone morphogenic proteins). Burt, Evolutionary grouping of the transforming growth factor-beta superfamily. Biochem. Biophys. Res. Commun. 184:590-5 (1992).
Some 23 fibroblast growth factors identified to date (FGFs 1-23). Peptides from natural HBGFs that bind heparin-binding growth factor receptors have been identified. See for example Ray et al., Proc. Natl. Acad. Sci. USA 94:7047-7052 (1997). FGFs useful in prevention or therapy of a wide range of diseases and disorders may be purified from natural sources or produced by recombinant DNA methods; however, such preparations are expensive and generally difficult to prepare.
However, there are no known formulations, methods or kits designed to provide components that augment or activate growth factors, such as FGF-2, BMP-2 or TGF-β, which may be present endogenously, such as produced by the individual being treatment, or which may be exogenous, such as derived from natural material or produced by recombinant means. There are further no known formulations, methods or kits that employ the synthetic heparin-binding growth factor analogs disclosed herein. It is against this background that the invention is made.